The efficacy of treating neurodegerative disorders with transplantation of human fetal tissue has been shown in animal models [Brundin, et al, Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease, Exp Brain Res, 65 (1986) 235-40.; Wictorin et al, Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts, Nature, 347 (1990) 556-8.] as well as in patients with Parkinson's disease (PD) and Huntington's disease [Bachoud-Levi et al, Motor and cognitive improvements in patients with Huntington's disease after neural transplantation, Lancet, 356 (2000) 1975-9.; Freed et al, Transplantation of embryonic dopamine neurons for severe Parkinson's disease, N Engl J Med, 344 (2001) 710-9.; Hagell et al, Sequential bilateral transplantation in Parkinson's disease: effects of the second graft, Brain, 122 (Pt 6) (1999) 1121-32.; Kordower et al, Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease, N Engl J Med, 332 (1995) 1118-24.; Lindvall et al, Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease, Science, 247 (1990) 574-7; Olanow et al, Fetal nigral transplantation as a therapy for Parkinson's disease, Trends Neurosci, 19 (1996) 102-9.]. However, human-derived fetal donor cells gives rise to both ethical and practical dilemmas, and therefore, alternative cell sources for future transplantations have to be developed. Implantation of cells genetically modified to express therapeutic genes into the brain has been proposed as a potential treatment for neurodegenerative disorders [Villa, A., Navarro, B. and Martinez-Serrano, A., Genetic perpetuation of in vitro expanded human neural stem cells: cellular properties and therapeutic potential, Brain Res Bull, 57 (2002) 789-94.]. Thus, when combining genetic engineering and cell transplantation, an important issue is to find a suitable cell vehicle.
Tumour cells modified to express a Thymidine Kinase (TK) gene acquire the ability to convert the non-toxic nucleoside analog ganciclovir (GCV) to its cytotoxic metabolite ganciclovir-triphosphate. Cells genetically engineered to express this “suicide” gene are eliminated if exposed to ganciclovir. Experimental tissue culture of tumour cells as well as brain tumour implants, consisting of a mixture of TK-expressing cells and unmodified “native” tumour cells also regress following ganciclovir treatment without harm to adjacent normal tissue. This phenomenon, where a minority of TK-expressing cells lead to the death and elimination of adjacent native tumour cells not expressing TK, has been termed the “bystander effect”.
Malignant brain tumours are an appealing target for suicide gene delivery, since the entire malignancy is confined to the brain and amenable to eradication by the bystander effect. Key components for the success of this strategy are the genetic vector from which the suicide gene is expressed and its delivery vehicle. As it is impossible to target all individual tumours in e.g. glioblastoma multiforme with separate injections of a gene therapy vector another delivery strategy is needed. Migrating cells that are capable of tracking down glioma cells and that have been engineered to deliver a therapeutic molecule represent an ideal solution to the problem of glioma cells invading normal brain tissue. It has been demonstrated that the migratory capacity of neural stem cells (NSCs) is ideally suited to therapy in neurodegenerative disease models that require brain-wide cell replacement and gene expression. It has been hypothesized that NSCs may specifically home to sites of disease within the brain. Studies have also yielded the intriguing observation that transplanted NSCs are able to home into a primary tumour mass when injected at a distance from the tumour itself; furthermore, NSCs were observed to distribute themselves throughout the tumour bed, even migrating in juxtaposition to advancing single tumour cells (Dunn & Black, Neurosurgery 2003, 52:1411-1424; Aboody et al, PNAS, 2000, 97:12846-12851). These authors showed that NSCs were capable of tracking infiltrating glioma cells in the brain tissue peripheral to the tumour mass, and “piggy back” single tumour cells to make cell-to-cell-contact.
The present invention addresses several problems in the area of treatment of neurodegenerative disorders and in the treatment of cancer It is thus one object of the invention to provide sufficient material for replacement cell therapy obviating the need for large amounts of foetal tissue. It is another object to provide cells capable of stably expressing transgenes after transplantation into the CNS. It is a further object to provide cells capable of forming gap junctions with cancer cells. It is also an object to provide cells capable of tracing cancer cells in the CNS. Finally, such cells should be able to proliferated such that they can be passaged enough to be expanded, transfected with therapeutic genes and banked.